CA1133011A - METHOD FOR CHLORINATING THE CARBOXYLIC GROUP OF .alpha.-AMINOACIDS - Google Patents
METHOD FOR CHLORINATING THE CARBOXYLIC GROUP OF .alpha.-AMINOACIDSInfo
- Publication number
- CA1133011A CA1133011A CA346,231A CA346231A CA1133011A CA 1133011 A CA1133011 A CA 1133011A CA 346231 A CA346231 A CA 346231A CA 1133011 A CA1133011 A CA 1133011A
- Authority
- CA
- Canada
- Prior art keywords
- hydroxyphenyl
- chlorinating
- glycine
- dioxane
- hydrochloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 238000000034 method Methods 0.000 title claims abstract description 19
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 14
- KKLMJYDGZSAIQX-UHFFFAOYSA-N 2-(n-hydroxyanilino)acetic acid Chemical compound OC(=O)CN(O)C1=CC=CC=C1 KKLMJYDGZSAIQX-UHFFFAOYSA-N 0.000 claims abstract 5
- ZAKRZZDABWCUGW-UHFFFAOYSA-N 2-aminoacetyl chloride;hydrochloride Chemical compound Cl.NCC(Cl)=O ZAKRZZDABWCUGW-UHFFFAOYSA-N 0.000 claims abstract 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 9
- LJCWONGJFPCTTL-UHFFFAOYSA-N 4-hydroxyphenylglycine Chemical group OC(=O)C(N)C1=CC=C(O)C=C1 LJCWONGJFPCTTL-UHFFFAOYSA-N 0.000 claims description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000012453 solvate Substances 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 229910006124 SOCl2 Inorganic materials 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- 150000005840 aryl radicals Chemical class 0.000 claims 1
- 235000001014 amino acid Nutrition 0.000 abstract description 6
- 239000012320 chlorinating reagent Substances 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 150000001413 amino acids Chemical class 0.000 abstract description 5
- -1 cyclic anhydride Chemical class 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000002329 infrared spectrum Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000005660 chlorination reaction Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 3
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- LJCWONGJFPCTTL-SSDOTTSWSA-N D-4-hydroxyphenylglycine Chemical compound [O-]C(=O)[C@H]([NH3+])C1=CC=C(O)C=C1 LJCWONGJFPCTTL-SSDOTTSWSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 150000001263 acyl chlorides Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- MRFJAULKKHVIGF-UHFFFAOYSA-N 2-amino-2-(4-hydroxyphenyl)acetyl chloride;hydrochloride Chemical compound [Cl-].ClC(=O)C([NH3+])C1=CC=C(O)C=C1 MRFJAULKKHVIGF-UHFFFAOYSA-N 0.000 description 1
- 241001156002 Anthonomus pomorum Species 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- ZGUNAGUHMKGQNY-UHFFFAOYSA-N alpha-phenylglycine Chemical compound OC(=O)C(N)C1=CC=CC=C1 ZGUNAGUHMKGQNY-UHFFFAOYSA-N 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 150000002960 penicillins Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000003381 solubilizing effect Effects 0.000 description 1
- 239000011877 solvent mixture Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
- C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
"IMPROVED METHOD FOR CHLORINATING THE CARBOXYLIC GROUP
OF .alpha.-AMINOACIDS"
Abstract of the disclosure A method for chlorinating the carboxylic group of .alpha.- aminoacids (e.g. hydroxyphenyl-glycine) is described wherein the aminoacid is suspended in an optionally solvate-forming solvent, treated with an excess of gaseous HCl and then with a chlorinating agent having the general formula [SOaCl2.R1R2NCHO] (e-g. SO Cl2.(CH3)2NcHo).
A typical compound thus obtained is the dioxane hemisolvate of D(-)2-(p-hydroxyphenyl)glycyl chloride hydrochloride.
OF .alpha.-AMINOACIDS"
Abstract of the disclosure A method for chlorinating the carboxylic group of .alpha.- aminoacids (e.g. hydroxyphenyl-glycine) is described wherein the aminoacid is suspended in an optionally solvate-forming solvent, treated with an excess of gaseous HCl and then with a chlorinating agent having the general formula [SOaCl2.R1R2NCHO] (e-g. SO Cl2.(CH3)2NcHo).
A typical compound thus obtained is the dioxane hemisolvate of D(-)2-(p-hydroxyphenyl)glycyl chloride hydrochloride.
Description
11330~1 Field of the invention The present invention relates to an improved method for chlorinating the carboxylic group of -aminoacids, particularly p-hydroxyphenylglycine and 2-phenylglycine, as well as of the relevant derivatives.
Background of the invention The chlorination of the carboxylic qroup of q -aminoacids by means of the usual chlorinating agents such as PC15, PC13, C12, SOC12, etc. often presents synthesis difficulties due both to the steric hindrance and to the presence of various substituents. Among the hardly chlorinatable aminoacids there is for instance included p-hydroxyphenylglycine, since, among other things, the presence of a hydroxyl group on the benzene ring considerably disturbs the production of acyl chloride and besides the obtention of the product in crystalline and stable form is difficult, which form is necessary for an effective recovering from the reaction mixture.
Among the many attempts aiming at attaining the chlorination on the carboxylic group of p-OH-phenylglycine, two processes had a certain success, The first of them, which is based on the use of phosgene as the chlorinating agent and described in US Patent 3925~18 as well as by Brenner and Photaki in ~Ae1v, Chimica Acta, 1956, pages 1525-26, is rather complex as it consists in forming a cyclic anhydride and successively cleaving with gaseous hydrogen chloride, and further requires the use of phosgene, which gives rise to noticeable plant problems due to its dangerous nature and corrosivity. The second process is based on the use of cnloromethylene-dimethylammonium chloride as the chlorinating agent and is described in Ca~adian Patent No. 1,115,731 of R~ Maggi et al, granted January 5, 1982.
3Ul~
Summary of the invention The applicant company, in the course of its studies on the obtention of chlorides of a-aminoacids and particularly of 2-(p-hydroxyphenyl)glycine, has developed a chlorinating process which provides a good and practical novel method for preparing the desired hydrochloride chloro derivatives with high purity.
Such a high purity degree is essential, as the products obtained by this novel process have been found to have physico-chemical properties which are suitable for the productionof ~emi-synthetic penicillins and cephalosporins-The chlorination process according to the present inventioninvolves the use of chlorinating agents of the type XC12 . NCH0 (I) wherein X can be S0 and S02; R1 and R2 can be, each other independently, low alkyl groups such as CH3, C2H5 etc., or aryl groups such as C6H5.
The use of adducts of type (I) has been unexpectedly found to be satisfactory e.g. in the chlorination of 2-(p-hydroxy-phenyl)glycine under mild condition~. The type (I) adducts can be prepared by reacting equimolar amounts of XC12 and R1R2NCH0 at low temperature. The a-aminoacid, in particular
Background of the invention The chlorination of the carboxylic qroup of q -aminoacids by means of the usual chlorinating agents such as PC15, PC13, C12, SOC12, etc. often presents synthesis difficulties due both to the steric hindrance and to the presence of various substituents. Among the hardly chlorinatable aminoacids there is for instance included p-hydroxyphenylglycine, since, among other things, the presence of a hydroxyl group on the benzene ring considerably disturbs the production of acyl chloride and besides the obtention of the product in crystalline and stable form is difficult, which form is necessary for an effective recovering from the reaction mixture.
Among the many attempts aiming at attaining the chlorination on the carboxylic group of p-OH-phenylglycine, two processes had a certain success, The first of them, which is based on the use of phosgene as the chlorinating agent and described in US Patent 3925~18 as well as by Brenner and Photaki in ~Ae1v, Chimica Acta, 1956, pages 1525-26, is rather complex as it consists in forming a cyclic anhydride and successively cleaving with gaseous hydrogen chloride, and further requires the use of phosgene, which gives rise to noticeable plant problems due to its dangerous nature and corrosivity. The second process is based on the use of cnloromethylene-dimethylammonium chloride as the chlorinating agent and is described in Ca~adian Patent No. 1,115,731 of R~ Maggi et al, granted January 5, 1982.
3Ul~
Summary of the invention The applicant company, in the course of its studies on the obtention of chlorides of a-aminoacids and particularly of 2-(p-hydroxyphenyl)glycine, has developed a chlorinating process which provides a good and practical novel method for preparing the desired hydrochloride chloro derivatives with high purity.
Such a high purity degree is essential, as the products obtained by this novel process have been found to have physico-chemical properties which are suitable for the productionof ~emi-synthetic penicillins and cephalosporins-The chlorination process according to the present inventioninvolves the use of chlorinating agents of the type XC12 . NCH0 (I) wherein X can be S0 and S02; R1 and R2 can be, each other independently, low alkyl groups such as CH3, C2H5 etc., or aryl groups such as C6H5.
The use of adducts of type (I) has been unexpectedly found to be satisfactory e.g. in the chlorination of 2-(p-hydroxy-phenyl)glycine under mild condition~. The type (I) adducts can be prepared by reacting equimolar amounts of XC12 and R1R2NCH0 at low temperature. The a-aminoacid, in particular
2-(p-hydroxyphenyl)glycine,is suspended in organic solvents and the suspension is treated with hydrochloric acid to give the hydrochloride of the aminoacid. By reacting this suspension with the chlorinating agent of type (I) under mild temperature conditions the acyl chloride is obtained which can easily be recovered from the reaction mixture.
The organic solvents which are suitable to the process according to this invention should have a substantial chemical
The organic solvents which are suitable to the process according to this invention should have a substantial chemical
- 3 -.
~330~
inertness towards bo~h the adduct (I) and 2-(p-hydroxyphenyl)-glycine and should further be capable of selectively insolubilizing the desired chlorination product with a high degree of purity.
Examples of suitable solvents comprise acetonitrile, tetrahydrofurane, benzene, toluene, n-hexane, dioxane, ethyl acetate, dichloromethane, chloroform and dichloroethane.
The preferred solvent in order to get good yields is dioxane or a mixture of dioxane with one or more of the other listed solvents. It has been found that dioxane has not only a suspending or solubilizing function with respect to 2-(p-hydroxyphenyl)-glycine, but also a stabilizing function of the final product due to the formation of a hemisolvate of 2-(p-hydroxyphenyl)-glycyl-chloride hydrochloride.
Besides it has turned out that also the use of acetonitrile as the reaction solvent allows one to obtain the chlorinated product firmly solvated with one mole of acetonitrile.
Description of the preferred embodiment The present invention will now be further described with reference to some embodying examples given for illustrative and non-limiting purposes.
Example 1 - Preparation of the adduct ~SOCl2.(CH3)2NCH0]
In a flask equipped with a stirrer, thermometer and thermostatic bath 119.2 g (1 mole) of thionyl chloride are charged, cooled to 0C,and 73.1 g (1 mole) of N,N-dimethylformamide are added under stirring,yet maintaining the temperature below 5C. At the end of the addition the temperature is allowed to rise up to 20C and then maintained constant for at least 3 hours.
192 g of a yellow oily liquid which is extremely reactive 30 with atmospheric moisture are obtained.
Example 2 - Preparation of the adduct ~S02Cl2(CH3)2NCH0l In a flask equipped with a stirrer, thermometer and thermostatic bath 135 g (1 mole) of sulphuryl chloride are charged, cooled to 0C,and 73.1 g (1 mole) of N,N-dimethylformamide are added under stirring,yet maintaining the temperature below 5~C.
At the end of the addition the temperature is allowed to rise up to 20C and maintained constant for at least 3 hours.
208 g of ~S02Cl2.(CH3)2NCHO~ as a oily liquid are obtained.
Example 3 - Preparation of the hydrochloride of D(-)2-(p-hydroxyphenyl)glycyl chloride hemisolvate with dioxane.
In a flask equipped with stirrer, thermometer and thermo-static bath 50 g (0.3 mole) o~ D(-)2-(p-hydroxyphenyl)glycine are suspended in 150 ml dioxane; the suspension is treated at room temperature with gaseous HCl to give the hydrochloride of the aminoacid hemisolvate.
Upon cooling to 10C 75 g (0.3~ mole) of adduct (I) prepared according to Example 1 are charged.
Once the addition is ended the mixture is heated up to 20-30C for 15 minutes.
The reaction mass is cooled to 20C and optionally seeded with 500 mg of the previously obtained crystalline chlorinated compound. Once the crystallization is ended the mixture is cooled down to 0C to which 100 ml dichloromethane are added, and the crystallization is further allowed for 4 hours. The crystalline precipitate thus obtained is filtered, washed with dioxane and dichloromethane and dried under vacuum at 30C.
Abo~t 60 g (0.225 mole) of the hydrochloride of D(-)2(p-hydroxyphe nyl)glycyl chloride hemisolvate are obtained having an IR spectrum according to the standards and a titer of 93.5% without solvent.
..,~
'~
.~
11330~
Example 4 - Preparation of the hydrochloride of D(-)2(p-hydroxyphenyl)glycyl chloride hemisolvate with acetonitrile.
50 g of D(-)2(p-hydroxyphenyl)glycine are suspended in a solvent mixture of 50 ml dioxane and 100 ml acetonitrile, to which gaseous HCl is added at room temperature up to saturation thus obtaining the hydrochloride of the aminoacid solvate. 75 g of adduct (I) are slowly added at 10C and then heated up to 25C for 15 minutes.
The mixture is slowly cooled thus causing the spontaneous crystallization of the chlorinated product. The reaction mixture is maintained at 0C for 4 hours in order to complete the crystallization.
The compound is recovered by filtration, washed with acetonitrile and dried under vacuum. About 58 g of the desired chlorinated compound solvated with acetonitrile are obtained. The IR spectrum shows that the product has a high purity degree; titre without solvent: 96%.
Example 5 - Preparation of the hydrochloride of D(-)2(p-hydroxyphenyl)glycyl chloridé hemisolvate with dioxane.
The process of Examples 3 and 4 is repeated except that a mixture of solvents consisting of 100 ml dioxane and 50 ml CH2Cl2 was used. 60 g of the hydrochloride of D(-)2(p-hydroxyphenyl)glycyl chloride hemisolvate are obtained.
Titre without solvent: 94%. IR spectrum according to standards.
Example 6 The process of Examp~es 3, 4 and 5 is followed except that a mixture of solvents consisting of 100 ml dioxane and 50 ml benzene is used.
54 g of the desired chlorinated compount are obtained having a titre of 93.5% without solvent and an IR spectrum ll3ao~
according to standards.
Example 7 The process according to Examples 3, 4, 5 and 6 is repeated except that a mixture consisting of 100 ml dioxane and 50 ml n-hexane is used.
54 g of the desired chlorinated compound are obtained having a titre of 92.5% without solvent and an IR spectrum according to standards.
Example 8 The process of Examples 3 to 7 is repeated except that a mixture of solvents consisting of 100 ml dioxane and 100 ml ethyl acetate is used instead. 50 g of the desired chlorinated compound are obtained. The titre without solvent is 93% and the IR spectrum conforms to standards.
~ E~
~330~
inertness towards bo~h the adduct (I) and 2-(p-hydroxyphenyl)-glycine and should further be capable of selectively insolubilizing the desired chlorination product with a high degree of purity.
Examples of suitable solvents comprise acetonitrile, tetrahydrofurane, benzene, toluene, n-hexane, dioxane, ethyl acetate, dichloromethane, chloroform and dichloroethane.
The preferred solvent in order to get good yields is dioxane or a mixture of dioxane with one or more of the other listed solvents. It has been found that dioxane has not only a suspending or solubilizing function with respect to 2-(p-hydroxyphenyl)-glycine, but also a stabilizing function of the final product due to the formation of a hemisolvate of 2-(p-hydroxyphenyl)-glycyl-chloride hydrochloride.
Besides it has turned out that also the use of acetonitrile as the reaction solvent allows one to obtain the chlorinated product firmly solvated with one mole of acetonitrile.
Description of the preferred embodiment The present invention will now be further described with reference to some embodying examples given for illustrative and non-limiting purposes.
Example 1 - Preparation of the adduct ~SOCl2.(CH3)2NCH0]
In a flask equipped with a stirrer, thermometer and thermostatic bath 119.2 g (1 mole) of thionyl chloride are charged, cooled to 0C,and 73.1 g (1 mole) of N,N-dimethylformamide are added under stirring,yet maintaining the temperature below 5C. At the end of the addition the temperature is allowed to rise up to 20C and then maintained constant for at least 3 hours.
192 g of a yellow oily liquid which is extremely reactive 30 with atmospheric moisture are obtained.
Example 2 - Preparation of the adduct ~S02Cl2(CH3)2NCH0l In a flask equipped with a stirrer, thermometer and thermostatic bath 135 g (1 mole) of sulphuryl chloride are charged, cooled to 0C,and 73.1 g (1 mole) of N,N-dimethylformamide are added under stirring,yet maintaining the temperature below 5~C.
At the end of the addition the temperature is allowed to rise up to 20C and maintained constant for at least 3 hours.
208 g of ~S02Cl2.(CH3)2NCHO~ as a oily liquid are obtained.
Example 3 - Preparation of the hydrochloride of D(-)2-(p-hydroxyphenyl)glycyl chloride hemisolvate with dioxane.
In a flask equipped with stirrer, thermometer and thermo-static bath 50 g (0.3 mole) o~ D(-)2-(p-hydroxyphenyl)glycine are suspended in 150 ml dioxane; the suspension is treated at room temperature with gaseous HCl to give the hydrochloride of the aminoacid hemisolvate.
Upon cooling to 10C 75 g (0.3~ mole) of adduct (I) prepared according to Example 1 are charged.
Once the addition is ended the mixture is heated up to 20-30C for 15 minutes.
The reaction mass is cooled to 20C and optionally seeded with 500 mg of the previously obtained crystalline chlorinated compound. Once the crystallization is ended the mixture is cooled down to 0C to which 100 ml dichloromethane are added, and the crystallization is further allowed for 4 hours. The crystalline precipitate thus obtained is filtered, washed with dioxane and dichloromethane and dried under vacuum at 30C.
Abo~t 60 g (0.225 mole) of the hydrochloride of D(-)2(p-hydroxyphe nyl)glycyl chloride hemisolvate are obtained having an IR spectrum according to the standards and a titer of 93.5% without solvent.
..,~
'~
.~
11330~
Example 4 - Preparation of the hydrochloride of D(-)2(p-hydroxyphenyl)glycyl chloride hemisolvate with acetonitrile.
50 g of D(-)2(p-hydroxyphenyl)glycine are suspended in a solvent mixture of 50 ml dioxane and 100 ml acetonitrile, to which gaseous HCl is added at room temperature up to saturation thus obtaining the hydrochloride of the aminoacid solvate. 75 g of adduct (I) are slowly added at 10C and then heated up to 25C for 15 minutes.
The mixture is slowly cooled thus causing the spontaneous crystallization of the chlorinated product. The reaction mixture is maintained at 0C for 4 hours in order to complete the crystallization.
The compound is recovered by filtration, washed with acetonitrile and dried under vacuum. About 58 g of the desired chlorinated compound solvated with acetonitrile are obtained. The IR spectrum shows that the product has a high purity degree; titre without solvent: 96%.
Example 5 - Preparation of the hydrochloride of D(-)2(p-hydroxyphenyl)glycyl chloridé hemisolvate with dioxane.
The process of Examples 3 and 4 is repeated except that a mixture of solvents consisting of 100 ml dioxane and 50 ml CH2Cl2 was used. 60 g of the hydrochloride of D(-)2(p-hydroxyphenyl)glycyl chloride hemisolvate are obtained.
Titre without solvent: 94%. IR spectrum according to standards.
Example 6 The process of Examp~es 3, 4 and 5 is followed except that a mixture of solvents consisting of 100 ml dioxane and 50 ml benzene is used.
54 g of the desired chlorinated compount are obtained having a titre of 93.5% without solvent and an IR spectrum ll3ao~
according to standards.
Example 7 The process according to Examples 3, 4, 5 and 6 is repeated except that a mixture consisting of 100 ml dioxane and 50 ml n-hexane is used.
54 g of the desired chlorinated compound are obtained having a titre of 92.5% without solvent and an IR spectrum according to standards.
Example 8 The process of Examples 3 to 7 is repeated except that a mixture of solvents consisting of 100 ml dioxane and 100 ml ethyl acetate is used instead. 50 g of the desired chlorinated compound are obtained. The titre without solvent is 93% and the IR spectrum conforms to standards.
~ E~
Claims (6)
1. A method for chlorinating the carboxylic group of a hydroxyphenyl-glycine essentially comprising the steps of:
- suspending said hydroxyphenyl-glycine in at least one organic solvent;
- treating the obtained suspension with gaseous HCl at room temperature to give the hydrochloride of said hydroxyphenyl - glycine;
- chlorinating at 10° to 30°C the said hydrochloride with an adduct of general formula [XCl2.R1R2NCHO] wherein X is SO or SO2 and R1 and R2 are lower alkyl or aryl radicals.
- suspending said hydroxyphenyl-glycine in at least one organic solvent;
- treating the obtained suspension with gaseous HCl at room temperature to give the hydrochloride of said hydroxyphenyl - glycine;
- chlorinating at 10° to 30°C the said hydrochloride with an adduct of general formula [XCl2.R1R2NCHO] wherein X is SO or SO2 and R1 and R2 are lower alkyl or aryl radicals.
2. The method of claim 1, wherein said hydroxyphenyl-glycine is 2-(p-hydroxyphenyl)glycine.
3. The method of claim 1, wherein said adduct is [SOCl2.(CH3)2NCHO].
4. The method of claim 1, wherein said at least one organic solvent is selected from the group consisting of dioxane and mixtures of dioxane and one or more further solvents such as dichloromethane, benzene, acetonitrile, chloroform, dichloroethane, n-hexane and ethyl acetate.
5. An acetonitrile solvate of an .alpha.-aminoacyl chloride hydrochloride.
6. The solvate of claim 5 consisting of the acetonitrile solvate of D(-)2-(p-hydroxyphenyl)glycyl chloride hydrochloride.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22323/79A IT1113934B (en) | 1979-05-03 | 1979-05-03 | PERFECTED CLORURATION PROCEDURE OF THE ALPHA-AMINO ACIDS CARBOXYL GROUP |
| IT22323A/79 | 1979-05-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1133011A true CA1133011A (en) | 1982-10-05 |
Family
ID=11194666
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA346,231A Expired CA1133011A (en) | 1979-05-03 | 1980-02-22 | METHOD FOR CHLORINATING THE CARBOXYLIC GROUP OF .alpha.-AMINOACIDS |
Country Status (21)
| Country | Link |
|---|---|
| US (2) | US4369146A (en) |
| JP (1) | JPS55145645A (en) |
| AR (1) | AR224259A1 (en) |
| AT (1) | AT370084B (en) |
| BE (1) | BE881984A (en) |
| CA (1) | CA1133011A (en) |
| CH (1) | CH647498A5 (en) |
| DE (1) | DE3015513A1 (en) |
| DK (1) | DK58280A (en) |
| ES (1) | ES8103022A1 (en) |
| FI (1) | FI800692A (en) |
| FR (1) | FR2455573B1 (en) |
| GB (1) | GB2048244B (en) |
| HU (1) | HU182078B (en) |
| IE (1) | IE49641B1 (en) |
| IL (1) | IL59365A (en) |
| IT (1) | IT1113934B (en) |
| NL (1) | NL8000933A (en) |
| PT (1) | PT70895A (en) |
| SE (1) | SE8001037L (en) |
| YU (1) | YU43880A (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL9300422A (en) * | 1993-03-09 | 1994-10-03 | Westspur Investment Ltd | Process for the preparation of D - (-) - phenylglycine chloride hydrochloride. |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3925418A (en) * | 1974-06-19 | 1975-12-09 | Bristol Myers Co | Hemisolvate of D-(-)-2-(p-hydroxyphenyl)glycyl chloride hydrochloride and process |
| IT1096213B (en) * | 1978-05-16 | 1985-08-26 | Chimica Bulciago Srl | ALPHA-AMINO ACID CLORURATION PROCEDURE |
-
1979
- 1979-05-03 IT IT22323/79A patent/IT1113934B/en active
-
1980
- 1980-02-11 DK DK58280A patent/DK58280A/en unknown
- 1980-02-11 SE SE8001037A patent/SE8001037L/en not_active Application Discontinuation
- 1980-02-11 IL IL59365A patent/IL59365A/en unknown
- 1980-02-12 IE IE268/80A patent/IE49641B1/en unknown
- 1980-02-12 GB GB8004652A patent/GB2048244B/en not_active Expired
- 1980-02-14 NL NL8000933A patent/NL8000933A/en not_active Application Discontinuation
- 1980-02-15 FR FR8003374A patent/FR2455573B1/en not_active Expired
- 1980-02-18 YU YU00438/80A patent/YU43880A/en unknown
- 1980-02-18 AT AT0087580A patent/AT370084B/en not_active IP Right Cessation
- 1980-02-19 CH CH1344/80A patent/CH647498A5/en not_active IP Right Cessation
- 1980-02-20 ES ES488797A patent/ES8103022A1/en not_active Expired
- 1980-02-20 JP JP2038180A patent/JPS55145645A/en active Pending
- 1980-02-22 CA CA346,231A patent/CA1133011A/en not_active Expired
- 1980-02-28 BE BE0/199603A patent/BE881984A/en not_active IP Right Cessation
- 1980-03-03 PT PT70895A patent/PT70895A/en unknown
- 1980-03-06 FI FI800692A patent/FI800692A/en not_active Application Discontinuation
- 1980-03-12 AR AR280287A patent/AR224259A1/en active
- 1980-04-16 HU HU80926A patent/HU182078B/en unknown
- 1980-04-23 DE DE19803015513 patent/DE3015513A1/en not_active Withdrawn
-
1981
- 1981-05-07 US US06/261,516 patent/US4369146A/en not_active Expired - Fee Related
-
1982
- 1982-07-23 US US06/401,357 patent/US4435333A/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| ATA87580A (en) | 1982-07-15 |
| PT70895A (en) | 1980-04-01 |
| DK58280A (en) | 1980-11-04 |
| GB2048244B (en) | 1983-11-23 |
| CH647498A5 (en) | 1985-01-31 |
| IT7922323A0 (en) | 1979-05-03 |
| IL59365A0 (en) | 1980-05-30 |
| DE3015513A1 (en) | 1980-11-06 |
| HU182078B (en) | 1983-12-28 |
| US4435333A (en) | 1984-03-06 |
| BE881984A (en) | 1980-06-16 |
| GB2048244A (en) | 1980-12-10 |
| ES488797A0 (en) | 1981-02-16 |
| NL8000933A (en) | 1980-11-05 |
| US4369146A (en) | 1983-01-18 |
| YU43880A (en) | 1983-02-28 |
| AR224259A1 (en) | 1981-11-13 |
| AT370084B (en) | 1983-02-25 |
| IE800268L (en) | 1980-11-03 |
| JPS55145645A (en) | 1980-11-13 |
| SE8001037L (en) | 1980-11-04 |
| IT1113934B (en) | 1986-01-27 |
| FR2455573B1 (en) | 1985-09-06 |
| ES8103022A1 (en) | 1981-02-16 |
| FR2455573A1 (en) | 1980-11-28 |
| IE49641B1 (en) | 1985-11-13 |
| FI800692A (en) | 1980-11-04 |
| IL59365A (en) | 1984-01-31 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |